PDRN, a bioactive natural compound, ameliorates imiquimod‐induced psoriasis through Nf‐κB pathway inhibition and wnt/β‐catenin signaling modulation

Nuclear factor‐κB (NF‐κB) plays a central role in psoriasis and canonical Wnt/β‐catenin pathway blunts the immune‐mediated inflammatory cascade in psoriasis. Adenosine A2A receptor activation blocks NF‐κB and boosts the Wnt/β‐catenin signaling. PDRN (Polydeoxyribonucleotide) is a biologic agonist of the A2A receptor and its effects were studied in an experimental model of psoriasis. Psoriasis‐like lesions were induced by a daily application of imiquimod (IMQ) on the shaved back skin of mice for 7 days. Animals were randomly assigned to the following groups: Sham psoriasis challenged with Vaseline; IMQ animals challenged with imiquimod; and IMQ animals treated with PDRN (8 mg/kg/ip). An additional arm of IMQ animals was treated with PDRN plus istradefylline (KW6002; 25 mg/kg/ip) as an A2A antagonist. PDRN restored a normal skin architecture, whereas istradefylline abrogated PDRN positive effects, thus pointing out the mechanistic role of the A2A receptor. PDRN decreased pro‐inflammatory cytokines, prompted Wnt signaling, reduced IL‐2 and increased IL‐10. PDRN also reverted the LPS repressed Wnt‐1/β‐catenin in human keratinocytes and these effects were abolished by ZM241385, an A2A receptor antagonist. Finally, PDRN reduced CD3+ cells in superficial psoriatic dermis. PDRN anti‐psoriasis potential may be linked to a “dual mode” of action: NF‐κB inhibition and Wnt/β‐catenin stimulation.